Loss of dopamine neurons in the substantia nigra is one of the main pathological features of Parkinson's disease, leading to a marked reduction in dopamine function in this pathway. The symptoms of the disease typically do not show themselves until 80-90% of dopamine function has been lost.

The desired clinical effect of reducing psychotic symptoms is thought to be associated with blocking dopamine function in the mesolimbic pathway only. However, as many of these drugs are not selective, they block dopamine in all pathways. When this happens in the nigrostriatal pathway, similar movement problems to those found in Parkinson's disease can occur.